Cancer treatment

ABSTRACT

This invention is a method of treating cancer, including carcinomas and sarcomas through the administration of a pharmaceutical composition containing an aldehyde 5-oxo-1,2,4-triazine hydrazide derivative. The aldehyde 5-oxo-1,2,4-triazine hydrazide derivative is selected from the group consisting of those with the formula:  
                 
 
     wherein R and R 1  are independently selected from the group consisting of hydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms and wherein R 3  is selected from the group consisting of alkyl having 1 to 7 carbon atoms, cycloalkyl having up to 7 carbon atoms, and substituted alkyl having up to 12 carbons wherein the alkyl group is substituted with one more  
     halogen, hydroxy, amino, sulfhydryl or alkoxy having up to 10 carbon atoms, or  
                 
 
     wherein X is independently selected from hydrogen, alkyl of less than 7 carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 or less, pharmaceutical salt, prodrug, metabolites and mixtures thereof. Pharmaceutical compositions comprising these compounds and their use in various treatment methods are claimed. The compounds can be used in conjunction with other chemotherapeutic agents and potentiators. The corresponding hydrazine of the formula:  
                 
 
     wherein R and R 1  are independently selected from the group consisting of hydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms also have anticancer activity.

[0001] The present application is a continuation application of U.S.Ser. No. 09/627,611 filed Jul. 28, 2000, incorporated by referenceherein, and claims priority to said application under 35 U.S.C. 120.

TECHNICAL FIELD

[0002] A method of treating cancer, including carcinomas and sarcomas isclaimed. The pharmaceutical composition containing compounds is alsoclaimed.

BACKGROUND OF THE INVENTION

[0003] Cancers are a leading cause of death in animals and humans. Theexact cause of cancer is not known, but links between certain activitiessuch as smoking or exposure to carcinogens and the incidence of certaintypes of cancers and tumors has been shown by a number of researchers.

[0004] Many types of chemotherapeutic agents have been shown to beeffective against cancers and tumor cells, but not all types of cancersand tumors respond to these agents. Unfortunately, many of these agentsalso destroy normal cells. The exact mechanism of action of thesechemotherapeutic agents is not always known.

[0005] Despite advances in the field of cancer treatment the leadingtherapies to date are surgery, radiation and chemotherapy.Chemotherapeutic approaches are said to fight cancers that aremetastasized or ones that are particularly aggressive. Such cytocidal orcytostatic agents work best on cancers with large growth factors, i.e.,ones whose cells are rapidly dividing. To date, hormones, in particularestrogen, progesterone and testosterone, and some antibiotics producedby a variety of microbes, alkylating agents, and anti-metabolites formthe bulk of therapies available to oncologists. Ideally cytotoxic agentsthat have specificity for cancer and tumor cells while not affectingnormal cells would be extremely desirable. Unfortunately, none have beenfound and instead agents which target especially rapidly dividing cells(both tumor and normal) have been used.

[0006] The development of materials that would target tumor cells due tosome unique specificity for them would be a breakthrough. Alternatively,materials that were cytotoxic to tumor cells while exerting mild effectson normal cells is also desirable.

SUMMARY OF THE INVENTION

[0007] A method of treating cancer, in particular, treating cancers inwarm blooded animals and humans, comprising administering atherapeutically effective amount of a composition comprising one or morealdehyde 5-oxo-1,2,4-triazine hydrazide compounds selected from thegroup consisting of those having the formula:

[0008] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms and wherein R₃ is selected from the group consisting ofalkyl having 1 to 7 carbon atoms, cycloalkyl having up to 7 carbonatoms, and substituted alkyl having up to 12 carbons wherein the alkylgroup is substituted with one more

[0009] halogen, hydroxy, amino, sulfhydryl or alkoxy having up to 10carbon atoms, or

[0010] wherein X is independently selected from hydrogen, alkyl of lessthan 7 carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 orless.

[0011] The pharmaceutical salt, metabolite and prodrug of the aldehyde5-oxo-1,2,4-triazine hydrazide compounds can also be used.

[0012] One of the metabolites is the hydrazine, for example,4-hydro-5-oxo-1,2,4-triazin-3-yl hydrazine or the analogs having theformula:

[0013] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms are also claimed herein for anticancer activity.

[0014] The present invention also provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound as described above.

[0015] These compositions have been discovered to inhibit the growth ofcancer or other tumors in humans or animals by administration of atherapeutically effective amount of the composition, preferably byadministering an aldehyde 5-oxo-1,2,4-triazine hydrazide compound to thesite of the cancer.

[0016] More specifically, this invention provides an anti-cancercomposition comprising a pharmaceutical carrier and aldehyde5-oxo-1,2,4-triazine hydrazide derivative as defined herein along with amethod for treating such cancers.

DETAILED DESCRIPTION OF THE INVENTION

[0017] A. Definitions

[0018] As used herein, a “pharmaceutically acceptable” component is onethat is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation, and allergicresponse) commensurate with a reasonable benefit/risk ratio.

[0019] As used herein, the term “safe and effective amount” refers tothe quantity of a component that is sufficient to yield a desiredtherapeutic response without undue adverse side effects (such astoxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of this invention.By “therapeutically effective amount” is meant an amount of a compoundof the present invention effective to yield the desired therapeuticresponse. For example, an amount effective to delay the growth of or tocause a cancer, either a sarcoma or lymphoma, to shrink or notmetastasize. The specific safe and effective amount or therapeuticallyeffective amount will vary with such factors as the particular conditionbeing treated, the physical condition of the patient, the type of mammalbeing treated, the duration of the treatment, the nature of concurrenttherapy (if any), and the specific formulations employed and thestructure of the compounds or its derivatives.

[0020] As used herein, a “pharmaceutical salts” is salt of an aldehyde5-oxo-1,2,4-triazine hydrazide derivative which has been modified bymaking acid or base salts of the compounds. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as phenols. Preferably the salts are made using anorganic or inorganic acid. These preferred acid salts are chlorides,bromides, sulfates, nitrates, phosphates, sulfonates, formates,tartrates, maleates, malates, citrates, benzoates, salicylates,ascorbates, and the like. The preferred phenolate salts are the alkalineearth metal salts, sodium, potassium or lithium.

[0021] As used herein, a “pharmaceutical carrier” is a pharmaceuticallyacceptable solvent, suspending agent or vehicle, for delivering thealdehyde 5-oxo-1,2,4-triazine hydrazide compound to the animal or human.The carrier may be liquid or solid and is selected with the plannedmanner of administration in mind. Liposomes are also a pharmaceuticalcarrier.

[0022] As used herein, “cancer” refers to all types of cancer orneoplasm or malignant tumors found in mammals, including carcinomas andsarcomas. Examples of cancers are cancer of the brain, breast, cervix,colon, head & neck, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.

[0023] The term “leukemia” refers broadly to progressive, malignantdiseases of the blood-forming organs and is generally characterized by adistorted proliferation and development of leukocytes and theirprecursors in the blood and bone marrow. Leukemia is generallyclinically classified on the basis of (1) the duration and character ofthe disease- acute or chronic; (2) the type of cell involved; myeloid(myelogenous), lymphoid (lymphogenous), or monocytic; and (3) theincrease or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). The P388 leukemia model is widelyaccepted as being predictive of in vivo anti-leukemic activity. It isbelieved that compound that tests positive in the P388 assay willgenerally exhibit some level of anti-leukemic activity in vivoregardless of the type of leukemia being treated. Accordingly, thepresent invention includes a method of treating leukemia, and,preferably, a method of treating acute nonlymphocytic leukemia, chroniclymphocytic leukemia, acute granulocytic leukemia, chronic granulocyticleukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemicleukemia, a leukocythemic leukemia, basophylic leukemia, blast cellleukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis,embryonal leukemia, cosinophilic leukemia, Gross' leukemia, hairy-cellleukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocyticleukemia, stem cell leukemia, acute monocytic leukemia, leukopenicleukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocyticleukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cellleukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblasticleukemia, monocytic leukemia, myeloblastic leukemia, myelocyticleukemia, myeloid granulocytic leukemia, myelomonocytic leukemia,Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia,promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stemcell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0024] The term “sarcoma” generally refers to a tumor which is made upof a substance like the embryonic connective tissue and is generallycomposed of closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas which can be treated with aldehyde5-oxo-1,2,4-triazine hydrazide and optionally a potentiator and/orchemotherapeutic agent include a chondrosarcoma, fibrosarcoma,lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy'ssarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma,ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma,stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma,giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathicmultiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of Bcells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma,Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma,malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocyticsarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, andtelangiectaltic sarcoma.

[0025] The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas which can betreated with aldehyde 5-oxo-1,2,4-triazine hydrazide and optionally apotentiator and/or another chemotherapeutic agent include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, and superficial spreading melanoma.

[0026] The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas which can be treated withaldehyde 5-oxo-1,2,4-triazine hydrazide and optionally a potentiatorand/or a chemotherapeutic agent include, for example, acinar carcinoma,acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma,carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma,alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare,basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolarcarcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriformcarcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloidcarcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma,carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma,cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonalcarcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinomaepitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere,carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giantcell carcinoma, carcinoma gigantocellulare, glandular carcinoma,granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma,hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma,hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma insitu, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelialcarcinoma, carcinoma medullare, medullary carcinoma, melanoticcarcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum,carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum,mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oatcell carcinoma, carcinoma ossificans, osteoid carcinoma, papillarycarcinoma, periportal carcinoma, preinvasive carcinoma, prickle cellcarcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reservecell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma,scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma,carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidalcell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamouscarcinoma, squamous cell carcinoma, string carcinoma, carcinomatelangiectaticum, carcinoma telangiectodes, transitional cell carcinoma,carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, andcarcinoma villosum.

[0027] Additional cancers which can be treated with aldehyde5-oxo-1,2,4-triazine hydrazide according to the invention include, forexample, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, breast cancer, ovarian cancer, lung cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,small-cell lung tumors, primary brain tumors, stomach cancer, coloncancer, malignant pancreatic insulanoma, malignant carcinoid, urinarybladder cancer, premalignant skin lesions, testicular cancer, lymphomas,thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tractcancer, malignant hypercalcemia, cervical cancer, endometrial cancer,adrenal cortical cancer, and prostate cancer.

[0028] As used herein, the “aldehyde 5-oxo-1,2,4-triazine hydrazidederivative” or “aldehyde 5-oxo-1,2,4-triazine hydrazide compound” arerefer to one or more of compounds having the generic formula:

[0029] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms and wherein R₃ is selected from the group consisting ofalkyl having 1 to 7 carbon atoms, cycloalkyl having up to 7 carbonatoms, and substituted alkyl having up to 12 carbons wherein the alkylgroup is substituted with one more halogen, hydroxy, amino, sulfhydrylor alkoxy having up to 10 carbon atoms, or

[0030] wherein X is independently selected from hydrogen, alkyl of lessthan 7 carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 orless. Preferably R₃ is

[0031] and X is hydrogen, chloro, fluoro, hydroxy or suflhydry and n is1 to 3. This term includes prodrug, salt and metabolite products of thealdehyde 5-oxo-1,2,4-triazine hydrazide.

[0032] As used herein, the term “metabolite” refers to the break-down orend product of a benzimidazole derivative compound or its salt producedby metabolism or biotransformation in the animal or human body; e.g.,biotransformation to a more polar molecule such as by oxidation,reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman “ThePharmacological Basis of Therapeutics” 8^(th) ed., Pergamon Press,Gilman et al. (eds), 1990 for a discussion of biotransformation). Asused herein, the metabolite of a benzimidazole derivative compound orits salt may be the biologically active form of the compound in thebody. An assay for activity of a metabolite of a benzimidazolederivative of the present invention is known to one of skill in the artin light of the present disclosure, for example, testing for efficacyagainst a virus in vitro or in vivo.

[0033] By “alkyl” as used herein is meant a straight, branched or cyclicalkane derivatives.

[0034] As used herein, the “5-oxo-1,2,4-triazine hydrazine derivative”or “5-oxo-1,2,4-triazine hydrazine compound” refer to one or more ofcompounds having the generic formula:

[0035] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms.

[0036] As used herein, the term “alkoxy” refers to an ether wherein thealkyl group is straight, branched or cyclic. The alkyl can be saturatedor unsaturated. Alkoxy includes polyglycol or polyglycerol derivatives.

[0037] As used herein “combination therapy” or “adjunct therapy” meansthat the patient in need of the drug is treated or given another drugfor the disease in conjunction with one or more aldehyde5-oxo-1,2,4-triazine hydrazide derivatives. This combination therapy canbe sequential therapy where the patient is treated first with one drugand then the other or the two drugs are given simultaneously.

[0038] B. Aldehyde 5-oxo-1,2,4-Triazine Hydrazide Compounds

[0039] The aldehyde 5-oxo-1,2,4-triazine hydrazide derivates have thefollowing structure:

[0040] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms and wherein R₃ is selected from the group consisting ofalkyl having 1 to 7 carbon atoms, cycloalkyl having up to 7 carbonatoms, and substituted alkyl having up to 12 carbons wherein the alkylgroup is substituted with one more halogen, hydroxy, amino, sulfhydrylor alkoxy having up to 10 carbon atom, or

[0041] wherein X is independently selected from hydrogen, alkyl of lessthan 7 carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 orless.

[0042] Preferred compounds have the structure:

[0043] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has 4 or lesscarbon atoms and X is independently selected from hydrogen, alkyl ofless than 7 carbons, halogen, amino, hydroxy and sulfhydryl and n is 2or less. Preferably R and R₁ are hydrogen or methyl and X is hydrogen,fluoro, chloro, alkyl of less than 4, hydroxyl or sulfhydryl.

[0044] The aldehyde 5-oxo-1,2,4-triazine hydrazide compounds alsoinclude prodrugs. “Prodrugs” are considered to be any covalently bondedcarriers which release the active parent drug according to the formulaof the aldehyde 5-oxo-1,2,4-triazine hydrazide compound(s) describedabove in vivo when such prodrug is administered to a mammalian subject.Prodrugs of the aldehyde 5-oxo-1,2,4-triazine hydrazide compounds areprepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compounds. Prodrugs include compounds whereinhydroxy, sulfhydryl, or amine groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl oramino group, respectively. Examples of prodrugs include, but are notlimited to, acetate, formate, or benzoate derivatives of alcohol andamine functional groups in the aldehyde 5-oxo-1,2,4-triazine hydrazideand phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters,aminoalkyl esters and carboxyalkyl esters of phenol functional groups inthe aldehyde 5-oxo-1,2,4-triazine hydrazide; and the like.

[0045] The pharmaceutically acceptable salts of the aldehyde5-oxo-1,2,4-triazine hydrazide include the conventional non-toxic saltsor the quaternary ammonium salts of the aldehyde 5-oxo-1,2,4-triazinehydrazide formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

[0046] The pharmaceutically acceptable salts of the present inventionare synthesized from the aldehyde 5-oxo-1,2,4-triazine hydrazidederivative(s) which contain a basic moiety by conventional chemicalmethods. Generally, such salts are prepared by reacting the free baseforms of these compounds with a stoichiometric amount of the appropriateacid in water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418.

[0047] Also included within the scope of the benzimidazole derivativesherein are active metabolites that are the break-down or final productof the benzimidazole derivatives, formed by metabolism orbiotransformation in the animal or human body. The metabolite may be thebiologically active form, rather than the benzimidazole derivativeitself.

[0048] The metabolites include the hydrazine compounds of the formula:

[0049] wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 7carbon atoms. Preferably R is hydrogen, methyl, ethyl or t-butyl and R₁is hydrogen.

SYNTHESIS

[0050] The aldehyde 5-oxo-1,2,4-triazine hydrazide derivatives areprepared in a number of ways well known to one skilled in the art oforganic synthesis. See for example, U.S. Pat. No. 3,077,473 issued to D.Liberman, 1963. The choice of the starting acid and the aldehyde used inthe final step will determine the substituents of the aldehyde5-oxo-1,2,4-triazine hydrazide. See the following sequence for a samplesynthesis of the 3-(5-oxo-1,2,4-triazinyl)hydrazone.

[0051] For example, 4-hydro-5 -oxo-1,2,4-triazin-3-yl hydrazine cansynthesized starting with glyoxylic acid as shown in the followingreaction sequence. The resulting 3-(5-oxo-1,2,4-triazinyl) hydrazine isreacted with 2-hydroxybenzaldehyde or benzaldehyde in presence of asuitable organic solvent, for example a low molecular with alcohol toproduce the corresponding hydrazide. In some cases an acid catalyst mayalso be used. Glyoxylic acid esters can be used. To make the substitutedmaterials, analogs of glyoxylic acid are used. For example, pyruvic acidwill yield the methyl derivative. Acetaldehyde, formaldehyde andbutyraldehyde can be used instead of benzaldehyde.

COMBINATION THERAPY

[0052] In some embodiments, aldehyde 5-oxo-1,2,4-triazine hydrazide isused in combination with one or more potentiators and/orchemotherapeutic agents for the treatment of cancer or tumors. Anexemplary potentiator is triprolidine or its cis-isomer which are usedin combination with chemotherapeutic agents and aldehyde5-oxo-1,2,3-triazine hydrazide. Triprolidine is described in U.S. Pat.No. 5,114,951 (1992). Another potentiator is procodazole,1H-Benzimidazole-2-propanoic acid; [β-(2-benzimidazole) propionic acid;2-(2-carboxyethyl)benzimidazole; propazol]. Procodazole is anon-specific immunoprotective agent active against viral and bacterialinfections that is used with the compositions claimed herein. It iseffective with aldehyde 5-oxo-1,2,4-triazine hydrazide in treatingcancers, tumors or leukemia. Procodazole can also be combined withaldehyde 5-oxo- 1,2,4-triazine hydrazide and other chemotherapeuticagents to treat cancer, tumor or leukemia.

[0053] Other potentiators which can be used with aldehyde5-oxo-1,2,4-triazine hydrazide and optionally another chemotherapeuticagent to treat or inhibit the growth of cancer include monensin, ananti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole,indomethacin, a monoclonal antibody, an anti-transferrin receptorimmunotoxin, metoclopramide, 7-thia-8-oxoguanosine,N-solanesyl-N,N′-bis(3,4-dimethoxybenzyl)ethylenediamine, leucovorin,heparin, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, heparinsulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxiccell cytotoxic agent, muramyl dipeptide, vitamin A, 2′-deoxycoformycin,a bis-diketopiperazine derivative, and dimethyl sulfoxide.

[0054] The chemotherapeutic agents which can be used with aldehyde5-oxo-1,2,4-triazine hydrazide and an optional potentiator are generallygrouped as DNA-interactive Agents, Antimetabolites, Tubulin-InteractiveAgents, Hormonal agents and others such as Asparaginase or hydroxyurea.Each of the groups of chemotherapeutic agents can be further divided bytype of activity or compound. The chemotherapeutic agents used incombination with aldehyde 5-oxo-1,2,4-triazine hydrazide include membersof all of these groups. For a detailed discussion of chemotherapeuticagents and their method of administration, see Dorr, et al, CancerChemotherapy Handbook, 2d edition, pages 15-34, Appleton & Lange(Connecticut, 1994).

[0055] DNA-Interactive Agents include the alkylating agents, e.g.Cisplatin, Cyclophosphamide, Altretamine; the DNA strand-breakageagents, such as Bleomycin; the intercalating topoisomerase IIinhibitors, e.g. Dactinomycin and Doxorubicin; the nonintercalatingtopoisomerase II inhibitors such as, Etoposide and Teniposde; and theDNA minor groove binder Plicamydin.

[0056] The alkylating agents form covalent chemical adducts withcellular DNA, RNA, and protein molecules and with smaller amino acids,glutathione and similar chemicals. Generally, these alkylating agentsreact with a nucleophilic atom in a cellular constituent, such as anamino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins,amino acids, or glutathione. The mechanism and the role of thesealkylating agents in cancer therapy is not well understood. Typicalalkylating agents include:

[0057] Nitrogen mustards, such as Chlorambucil, Cyclophosphamide,Isofamide, Mechlorethamine, Melphalan, Uracil mustard;

[0058] Aziridine such as Thiotepa;

[0059] methanesulphonate esters such as Busulfan;

[0060] nitroso ureas, such as Carmustine, Lomustine, Streptozocin;

[0061] platinum complexes, such as Cisplatin, Carboplatin;

[0062] bioreductive alkylator, such as Mitomycin, and Procarbazine,Dacarbazine and Altretamine.

[0063] DNA strand breaking agents include Bleomycin.

[0064] DNA topoisomerase II inhibitors include the following:

[0065] Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin,Doxorubicin, Idarubicin, and Mitoxantrone; and

[0066] nonintercalators, such as Etoposide and Teniposide.

[0067] The DNA minor groove binder is Plicamycin.

[0068] The antimetabolites interfere with the production of nucleicacids by one or the other of two major mechanisms. Some of the drugsinhibit production of the deoxyribonucleoside triphosphates that are theimmediate precursors for DNA synthesis, thus inhibiting DNA replication.Some of the compounds are sufficiently like purines or pyrimidines to beable to substitute for them in the anabolic nucleotide pathways. Theseanalogs can then be substituted into the DNA and RNA instead of theirnormal counterparts. The antimetabolites useful herein include:

[0069] folate antagonists such as Methotrexate and trimetrexate

[0070] pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine,CB3717, Azacitidine and Floxuridine

[0071] purine antagonists such as Mercaptopurine, 6-Thioguanine,Pentostatin;

[0072] sugar modified analogs such as Cytarabine and Fludarabine; and

[0073] ribonucleotide reductase inhibitors such as hydroxyurea.

[0074] Tubulin Interactive agents act by binding to specific sites ontubulin, a protein that polymerizes to form cellular microtubules.Microtubules are critical cell structure units. When the interactiveagents bind on the protein, the cell can not form microtubules TubulinInteractive agents include colchicine, Vincristine and Vinblastine, bothalkaloids and Paclitaxel and cytoxan.

[0075] Hormonal agents are also useful in the treatment of cancers andtumors. They are used in hormonally susceptible tumors and are usuallyderived from natural sources. These include:

[0076] estrogens, conjugated estrogens and Ethinyl Estradiol andDiethylstilbesterol, Chlortrianisen and Idenestrol;

[0077] progestins such as Hydroxyprogesterone caproate,Medroxyprogesterone, and Megestrol; and

[0078] androgens such as testosterone, testosterone propionate;fluoxymesterone, methyltestosterone.

[0079] Adrenal corticosteroids are derived from natural adrenal cortisolor hydrocortisone. They are used because of their anti inflammatorybenefits as well as the ability of some to inhibit mitotic divisions andto halt DNA synthesis. These compounds include, Prednisone,Dexamethasone, Methylprednisolone, and Prednisolone.

[0080] Leutinizing hormone releasing hormone agents orgonadotropin-releasing hormone antagonists are used primarily thetreatment of prostate cancer. These include leuprolide acetate andgoserelin acetate. They prevent the biosynthesis of steroids in thetestes.

[0081] Antihormonal antigens include:

[0082] antiestrogenic agents such as Tamoxifen,

[0083] antiandrogen agents such as Flutamide; and

[0084] antiadrenal agents such as Mitotane and Aminoglutethimide.

[0085] Hydroxyurea, which appears to act primarily through inhibition ofthe enzyme ribonucleotide reductase, can also be used in combinationwith aldehyde 5-oxo-1,2,4 triazine hydrazide.

[0086] Asparaginase is an enzyme which converts asparagine tononfunctional aspartic acid and thus blocks protein synthesis in thetumor. Asparaginase can also be used in combination with aldehyde5-oxo-1,2,4-triazine hydrazide to treat cancer.

DOSAGE

[0087] Aldehyde 5-oxo-1,2,4-triazine hydrazide, or5-oxo-1,2,4-triazinehydrazone or its pharmaceutical salt or prodrug ormetabolite is preferably micronized or powdered so that it is moreeasily dispersed and solubilized by the body. Processes for grinding orpulverizing drugs are well known in the art. For example, a hammer millor similar milling device are used. The preferred particle size is lessthan about 100μ and preferably less than 50μ.

[0088] Dosage forms (compositions) suitable for internal administrationcontain from about 1.0 milligram to about 5000 milligrams of activeingredient per unit. In these pharmaceutical compositions, the activeingredient will ordinarily be present in an amount of about 0.5 to about95% by weight based on the total weight of the composition. Based on thebody weight of the patient, the dosage may be administered in one ormore doses several times per day or per week. Multiple dosage units maybe required to achieve a therapeutically effective amount. For example,if the dosage form is 1000 mg, and the patient weighs 40 kg, one pillwill provide a dose of 25 mg per kg for that patient. It will provide adose of only 12.5 mg/kg for a 80 kg patient.

[0089] By way of general guidance, for humans a dosage of as little asabout 1 milligrams (mg) per kilogram (kg) of body weight and up to about10000 mg per kg of body weight is suitable as a therapeuticallyeffective dose. Preferably, from about 5 mg/kg to about 2500 mg/kg ofbody weight is used. Other preferred doses range between 25 mg/kg toabout 1000 mg/kg of body weight. However, a dosage of between about 2milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kgof body weight is also suitable for treating some cancers.

[0090] Intravenously, the most preferred rates of administration mayrange from about 1 to about 1000 mg/kg/minute during a constant rateinfusion. Aldehyde 5-oxo-1,2,4-triazine hydrazide may be administered ina single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily. Aldehyde5-oxo-1,2,4-triazine hydrazide is generally given in one or more doseson a daily basis or from one to three times a week.

[0091] Aldehyde 5-oxo-1,2,4-triazine hydrazide is administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or incombination with other therapeutic agents.

[0092] The amount and identity of a chemotherapeutic agent that is usedwith aldehyde 5-oxo-1,2,4-triazine hydrazide in treating cancer, tumor,leukemia, or other related diseases will vary according to patientresponse and physiology, type and severity of side effects, the diseasebeing treated, the preferred dosing regimen, patient prognosis or othersuch factors.

[0093] When aldehyde 5-oxo-1,2,4-triazine hydrazide is used incombination with other therapeutic agents, the ratio of aldehyde5-oxo-1,2,4-triazine hydrazide to the other therapeutic agent will bevaried as needed according to the desired therapeutic effect, theobserved side-effects of the combination, or other such considerationsknown to those of ordinary skill in the medical arts. Generally, theratio of aldehyde 5-oxo-1,2,4-triazine hydrazide to other therapeuticagent will range from about 0.5%: 99.5% to about 99.5%: 0.5% on a weightbasis.

[0094] When aldehyde 5-oxo-1,2,4-triazine hydrazide is administeredbefore or after other therapeutic agents to treat cancer, tumors, orother diseases, the respective doses and the dosing regimen of aldehyde5-oxo-1,2,4-triazine hydrazide and the other therapeutic agent may vary.The adjunct or combination therapy can be sequential, that is thetreatment with one agent first and then the second agent, or it can beconcomitant treatment wherein two or more agents are administeredsubstantially at the same time. The sequential therapy can be within areasonable time after the completion of the first therapy beforebeginning the second therapy. The treatment with both agents at the sametime can be in the same daily dose or in separate doses. For example,treatment with one agent on day 1 and the other on day 2. The exactregimen will depend on the disease being treated, the severity of thedisease and the response to the treatment.

[0095] For example, a full dosing regimen of aldehyde5-oxo-1,2,4-triazine hydrazide can be administered either before orafter a full dosing regimen of the other therapeutic agent, oralternating doses of aldehyde 5-oxo-1,2,4-triazine hydrazide and theother therapeutic agent may be administered. As a further example,aldehyde 5-oxo-1,2,4-triazine hydrazide can be administeredconcomitantly with the other therapeutic agent.

[0096] The identity of the chemotherapeutic agent, the pharmaceuticalcarrier and the amount of compound administered will vary widelydepending on the species and body weight of mammal and the type ofcancer being treated. The dosage administered will vary depending uponknown factors, such as the pharmacodynamic characteristics of a specificchemotherapeutic agent and its mode and route of administration; theage, sex, metabolic rate, absorptive efficiency, health and weight ofthe recipient; the nature and extent of the symptoms; the kind ofconcurrent treatment being administered; the frequency of treatmentwith; and the desired therapeutic effect.

[0097] Aldehyde 5-oxo-1,2,4-triazine hydrazide, the potentiator and/orthe chemotherapeutic agent are administered together in a single dosageform or separately in two or more different dosage forms. These can beadministered independently by the same route or by two or more differentroutes of administration depending on the dosage forms employed.

[0098] Suitable pharmaceutical compositions and dosage forms willpreferably comprise aldehyde 5-oxo-1,2,4-triazine hydrazide, apotentiator and optionally a chemotherapeutic agent. The ratio ofaldehyde 5-oxo-1,2,4-triazine hydrazide to potentiator is generally inthe range of about 1:.01 to 10:1, and preferably 1:.05 to 1:1 on aweight basis.

[0099] The dose and the range of chemotherapeutic agent will depend onthe particular agent and the type of cancer being treated. One skilledin the art will be able to ascertain the appropriate dose.

DOSAGE FORM

[0100] A dosage unit may comprise a single compound or mixtures thereofwith other anti-cancer compounds, other cancer or tumor growthinhibiting compounds. aldehyde 5-oxo-1,2,4-triazine hydrazide can beadministered in oral dosage forms as tablets, capsules, pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions.Aldehyde 5-oxo-1,2,4-triazine hydrazide may also be administered inintravenous (bolus or infusion), intraperitoneal, subcutaneous, orintramuscular form, all using dosage forms well known to those ofordinary skill in the pharmaceutical arts.

[0101] Aldehyde 5-oxo-1,2,4-triazine hydrazide is typically administeredin admixture with suitable pharmaceutical diluents, extenders,excipients, or carriers (collectively referred to herein as apharmaceutically acceptable carrier or carrier materials) suitablyselected with respect to the intended form of administration and asconsistent with conventional pharmaceutical practices. The unit will bein a form suitable for oral, rectal, topical, intravenous injection orparenteral administration.

[0102] Aldehyde 5-oxo-1,2,4-triazine hydrazide can be administered alonebut is generally mixed with a pharmaceutically acceptable carrier. Thiscarrier can be a solid or liquid, and the type of carrier is generallychosen based on the type of administration being used.

[0103] Specific examples of pharmaceutical acceptable carriers andexcipients that may be used to formulate oral dosage forms of thepresent invention are described in U. S. Pat. No. 3,903,297 to Robert,issued Sep. 2, 1975. Techniques and compositions for making dosage formsuseful in the present invention are described in the followingreferences: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al.,1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack PublishingCompany, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

[0104] Tablets may contain suitable binders, lubricants, disintegratingagents, coloring agents, flavoring agents, flow-inducing agents, andmelting agents. For instance, for oral administration in the dosage unitform of a tablet or capsule, the active drug component can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like.

[0105] Suitable binders include starch, gelatin, natural sugars such asglucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[0106] Aldehyde 5-oxo-1,2,4-triazine hydrazide can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamallar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0107] Aldehyde 5-oxo-1,2,4-triazine hydrazide may also be coupled tosoluble polymers as targetable drug carriers or as a prodrug. Suchpolymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, aldehyde5-oxo-1,2,4-triazine hydrazide may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyglycolic acid, copolymers ofpolylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacylates, and crosslinked or amphipathic block copolymers ofhydrogels.

[0108] The active ingredient can be administered orally in solid dosageforms, such as capsules, tablets, and powders, or in liquid dosageforms, such as elixirs, syrups, and suspensions. It can also beadministered parentally, in sterile liquid dosage forms.

[0109] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas immediate release products or as sustained release products toprovide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

[0110] For oral administration in liquid dosage form, the oral drugcomponents are combined with any oral, non-toxic, pharmaceuticallyacceptable inert carrier such as ethanol, glycerol, water, and the like.Examples of suitable liquid dosage forms include solutions orsuspensions in water, pharmaceutically acceptable fats and oils,alcohols or other organic solvents, including esters, emulsions, syrupsor elixirs, suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Such liquid dosage forms may contain, forexample, suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0111] Liquid dosage forms for oral administration can contain coloringand flavoring to increase patient acceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugarsolutions and glycols such as propylene glycol or polyethylene glycolsare suitable carriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

[0112] Aldehyde 5-oxo-1,2,4-triazine hydrazide may also be administeredin intranasal form via use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration willgenerally be continuous rather than intermittent throughout the dosageregimen.

[0113] Parenteral and intravenous forms may also include minerals andother materials to make them compatible with the type of injection ordelivery system chosen.

[0114] Useful pharmaceutical dosage forms for administration of aldehyde5-oxo-1,2,4-triazine hydrazide are illustrated as follows:

[0115] Capsules

[0116] A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 10 to 500 milligrams ofpowdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50milligrams of cellulose, and 6 milligrams magnesium stearate.

[0117] Soft Gelatin Capsules

[0118] A mixture of active ingredient in a digestible oil such assoybean oil, cottonseed oil or olive oil is prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100-500 milligrams of the active ingredient. Thecapsules are washed and dried.

[0119] Tablets

[0120] A large number of tablets are prepared by conventional proceduresso that the dosage unit was 100-500 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 50-275 milligrams of microcrystalline cellulose, 11 milligramsof starch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

[0121] Injectable Solution

[0122] A parenteral composition suitable for administration by injectionis prepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

[0123] Suspension

[0124] An aqueous suspension is prepared for oral administration so thateach 5 ml contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 ml of vanillin.

[0125] Kits

[0126] The present invention also includes pharmaceutical kits useful,for example, for the treatment of cancer, which comprise one or morecontainers containing a pharmaceutical composition comprising atherapeutically effective amount of aldehyde 5-oxo-1,2,4-triazinehydrazide. Such kits may further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Printed instructions, either as inserts or aslabels, indicating quantities of the components to be administered,guidelines for administration, and/or guidelines for mixing thecomponents, may also be included in the kit. It should be understoodthat although the specified materials and conditions are important inpracticing the invention, unspecified materials and conditions are notexcluded so long as they do not prevent the benefits of the inventionfrom being realized.

[0127] The chemotherapeutic agents, aldehyde 5-oxo-1,2,4-triazinehydrazide and, optionally, the potentiators are typically mixed with apharmaceutically acceptable carrier. This carrier can be a solid orliquid and the type is generally chosen based on the type ofadministration being used. The active agent can be coadministered in theform of a tablet or capsule, liposome, as an agglomerated powder or in aliquid form. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Capsule or tablets can be easily formulatedand can be made easy to swallow or chew; other solid forms includegranules, and bulk powders. Tablets may contain suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Examples of suitableliquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents. Oral dosage formsoptionally contain flavorants and coloring agents. Parenteral andintravenous forms may also include minerals and other materials to makethem compatible with the type of injection or delivery system chosen.

[0128] The 5-oxo-1,2,4-triazinyl hydrazones can be formulated in thesame dosage forms.

[0129] D. Method of Treatment

[0130] The method of treatment can be any suitable method that iseffective in the treatment of the particular cancer or tumor type beingtreated. Treatment may be oral, rectal, topical, parenteral orintravenous administration or by injection into the tumor or cancer. Themethod of applying an effective amount also varies depending on thedisorder or disease being treated. It is believed that parenteraltreatment by intravenous, subcutaneous, or intramuscular application ofaldehyde 5-oxo-1,2,4-triazine hydrazide, formulated with an appropriatecarrier, additional cancer inhibiting compound or compounds or diluentto facilitate application will be the preferred method of administeringthe compounds to warm blooded animals.

[0131] One skilled in the art will recognize that the efficacy of thecompounds can be ascertained through routine screening using knowncancer cell lines both in vitro and in vivo. Cell lines are availablefrom American Tissue Type Culture or other laboratories.

[0132] The following examples are illustrative and not intended to belimiting of the invention.

EXAMPLE 1

[0133] Each of the following compounds was tested for growth inhibitionin a MTT assay against B16 Murine Melanoma and HT29 Colon Cancer,reported as IC₅₀(μM). Compound HT-29 μM B16 μM I 0.007 0.264 II 0.0191.1

[0134] Compound I is benzaldehyde, 2-hydroxy-,(4-hydro-5-oxo-1,2,4-triazin-3-yl)hydrazide which has the formula:

[0135] Compound II is benzaldehyde, 2-hydroxy-,(4-hydro-5-oxo-6-methyl-1,2,4-triazin-3-yl)hydrazide that has theformula:

What is claimed is:
 1. A method of treating cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a composition comprising an aldehyde 5-oxo-1,2,4-triazinehydrazide compound selected from the group consisting of those with theformula:

wherein R and R₁ are independently selected from the group consisting ofhydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms andwherein R₃ is selected from the group consisting of alkyl having 1 to 7carbon atoms, cycloalkyl having up to 7 carbon atoms, and substitutedalkyl having up to 12 carbons wherein the alkyl group is substitutedwith one more halogen, hydroxy, amino, sulfhydryl or alkoxy having up to10 carbon atoms , or

wherein X is independently selected from hydrogen, alkyl of less than 7carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 or less,pharmaceutical salt, prodrug, metabolites and mixtures thereof.
 2. Amethod according to claim 1 wherein said cancer is prostate cancer.
 3. Amethod according to claim 1 wherein said cancer is breast cancer.
 4. Amethod according to claim 1 wherein said cancer is leukemia.
 5. A methodaccording to claim 1 wherein said cancer is pancreatic cancer.
 6. Amethod according to claim 1 wherein said cancer is lung cancer.
 7. Amethod according to claim 1 wherein said cancer is colon cancer.
 8. Amethod according to claim 1 wherein said cancer is a sarcoma.
 9. Amethod according to claim 1 wherein said cancer is a lymphoma.
 10. Amethod according to claim 1 wherein said aldehyde 5-oxo-1,2,4-triazinehydrazide compound is benzaldehyde, 2-hydroxy-,(4-hydro-5-oxo-1,2,4-triazin-3-yl)hydrazide or benzaldehyde, 2-hydroxy-,(4-hydro-5-oxo-6-methyl-1,2,4-triazin-3-yl)hydrazide, pharmaceuticalsalts and prodrug, metabolites thereof.
 11. A method according to claim1 wherein wherein R and R₁ are independently selected from the groupconsisting of hydrogen, or alkyl wherein the alkyl group has up to 4carbon atoms and wherein R₃ is

wherein X is independently selected from hydrogen, alkyl of less than 7carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 or less. 12.A pharmaceutical composition comprising a therapeutically effectiveamount of a composition comprising an aldehyde 5-oxo-1,2,4-triazinehydrazide compound selected from the group consisting of those with theformula:

wherein R and R₁ are independently selected from the group consisting ofhydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms andwherein R₃ is selected from the group consisting of alkyl having 1 to 7carbon atoms, cycloalkyl having up to 7 carbon atoms, and substitutedalkyl having up to 12 carbons wherein the alkyl group is substitutedwith one more halogen, hydroxy, amino, sulfhydryl or alkoxy having up to10 carbon atoms, or

wherein X is independently selected from hydrogen, alkyl of less than 7carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 or less,pharmaceutical salt, prodrug, metabolites and mixtures thereof.
 13. Apharmaceutical composition of claim 12 further comprising apharmaceutical carrier.
 14. A pharmaceutical composition according toclaim 12 wherein R₃ is

wherein X is independently selected from hydrogen, alkyl of less than 7carbons, halogen, amino, hydroxy and sulfhydryl and n is 4 or less. 15.A liposome composition comprising an aldehyde 5-oxo-1,2,4-triazinehydrazide compound selected from the group consisting of those with theformula:

wherein R and R₁ are independently selected from the group consisting ofhydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms andX is independently selected from hydrogen, alkyl of less than 7 carbons,halogen, amino, hydroxy and sulfhydryl and n is 4 or less,pharmaceutical salt, prodrug, metabolites and mixtures thereof.
 16. Aliposome composition according to claim 15 selected from the group ofconsisting of unilamallar vesicle and multilamallar vesicles.
 17. Aliposome composition according to claim 16 formed from phospholipidscholesterol, stearylamine or phosphatidyl choline.
 18. Thepharmaceutical composition of claim 12 wherein the aldehyde5-oxo-1,2,4-triazine hydrazide is a hydrochloride salt of benzaldehyde,2-hydroxy-, (4-hydro-5-oxo-1,2,4-triazin-3-yl)hydrazide or benzaldehyde,2-hydroxy-, (4-hydro-5-oxo-6-methyl-1,2,4-triazin-3-yl)hydrazide.
 19. Apharmaceutical composition comprising a therapeutically effective amountof a composition comprising an 5-oxo-1,2,4-triazine hydrazine compoundselected from the group consisting of those with the formula:

wherein R and R₁ are independently selected from the group consisting ofhydrogen, or alkyl wherein the alkyl group has up to 7 carbon atoms,pharmaceutical salt, prodrug, metabolites and mixtures thereof.
 20. Apharmaceutical composition of claim 19 further comprising apharmaceutical carrier.